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WO 2012/058097 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 3 May 2012 (03.05.2012) WO 2012/058097 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every CI2N 5/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US20 11/057140 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 20 October 201 1 (20.10.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (26) Publication Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (30) Priority Data: ZM, ZW. 61/455,808 26 October 2010 (26.10.2010) US 61/406,954 26 October 2010 (26.10.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): BUCK GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, INSTITUTE FOR AGE RESEARCH [US/US]; 8001 UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, Redwood Boulevard, Novate, California 94945 (US). RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, (72) Inventor; and LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, (75) Inventor/Applicant (for US only): LUNYAK, Victoria SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, V. [US/US]; 4 Shep Court, Novato, California 94945 GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (US). Published: (74) Agents: HUNTER, Tom et al; Weaver Austin Vil- leneuve & Sampson LLP, P.O. Box 70250, Oakland, Cal — with international search report (Art. 21(3)) ifornia 946 12-0250 (US). (54) Title: DOWNREGULATION OF SINE/ALU RETROTRANSPOSON TRANSCRIPTION TO INDUCE OR RESTORE PROLIFERATIVE CAPACITY AND/OR PLURIPOTENCY TO A STEM CELL Fig. 15A Senescent ADSC Lentivirus genome was modified to Viral particle express GFP and sh-RNA against Alu transcript Stable integration of viral genome ill upon infection © 00 © ADSC with stable knockdown of Alu RNA Lentivirus Generated Alu Knockdown o (57) Abstract: In certain embodiments methods are provided for inducing and/or restoring and/or maintaining a non-senescent phenotype, or aspects thereof (e.g., proliferative capacity and/or pluripotency) in a mammalian cell. The methods typically involve o reducing the level or activity of SINE/Alu retrotransposon transcripts in the cell in an amount sufficient to induce or restore prolif erative capacity and/or pluripotency to said mammalian cell. DOWNREGULATION OF SINE/ALU RETROTRANSPOSON TRANSCRIPTION TO INDUCE OR RESTORE PROLIFERATIVE CAPACITY AND/OR PLURIPOTENCY TO A STEM CELL CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and benefit of USSN 61/406,954, filed on October 26, 2010 and to USSN 61/455,808, filed on October 26, 2010 both of which are incorporated herein by reference in their entirety for all purposes. STATEMENT OF GOVERNMENTAL SUPPORT [ Not Applicable ] BACKGROUND [0002] Adult stem cells are extremely important for long-term tissue homeostasis throughout life. Their self-renewing proliferative capacity involves numerous tightly coordinated processes to ensure preservation of genome integrity during cell division. The regulatory mechanisms underlying their aging are less well defined. Nonetheless, global gene expression studies of stem cells purified from young and old mice have implicated the involvement of epigenetic regulation in higher-order chromatin dynamics. These studies have suggested coordinated age-dependent regulation of chromosomal regions, chromatin remodeling activities and lineage specification genes (Chambers et al. (2007) PLoS Biol., 5: e201; Rossi et al. (2007) Exp. Gerontol., 42: 385-390; Rossi et al. (2005) Proc. Natl. Acad. Sci. USA, 102: 9194-9199). [0003] All cells are constantly challenged by exogenous and endogenous sources of DNA damage; depending on the nature of the damage, they activate different DNA damage repair mechanisms (Sinclair et al. (2004) Am. Nat., 164: 396-414). In parallel, cells also activate checkpoint pathways, which delay cell cycle progression until genome integrity has been restored (Shiloh (2001) Curr. Opin. Genet. Dev., 11: 71-77). One aspect of the stem cell hypothesis of aging postulates that the gradual and coordinated age-related loss of DNA damage repair capacity results in DNA damage accumulation over time. This damage would pose a significant threat to adult stem cell survival by altering proliferation and differentiation patterns, ultimately triggering cellular senescence. Therefore, the ability of adult stem cells to monitor and faithfully repair DNA damage is key to the prevention of aging and neoplastic transformations. [0004] Little is known about the precise relationship between chromatin and DNA- repair factors. More than 50% of the human genome consists of retrotransposons (Lander et al. (2001) Nature, 409: 860-921). Their epigenetic makeup is poorly understood and inadequately annotated at the genomic level, due to a high degree of sequence conservation. In fact, many retrotransposons are derived from ancestral R A genes and might represent genetically active sequences that encode different types of RNA with yet unknown functions (McClintock (1956) Cold Spring Harb. Symp. Quant. Biol., 21: 197-216). However, clear evidence exists that the retrotransposal portion of the genome profoundly influences the organization, integrity, and evolution of the host's genome and transcriptome (Han et al. (2004) Nature, 429: 268-274; Kazazian (2004) Science, 303: 1626-1632). A growing body of evidence demonstrates that, during mammalian evolution, a large number of ancient retroelements acquired regulatory or structural functions. [0005] The majority of retrotransposons are expressed in extraordinarily complex patterns in a cell- or tissue-specific manner, and potentially provide a rich source of non- protein coding RNAs to guide the trajectories of cellular differentiation and multicellular development (Amaral et al. (2008) Science 319: 1787-1789; Birney etal. (2007) Nature, 447: 799-816; Denoeud et al. (2007) Genome Res., 17: 746-759; Dinger et al. (2008) GenomeRes., 18: 1433-1445; Dinger et al. (2008) J. Mol. Endocrinol., 40: 151-159; Emanuelsson et al. (2007) Genome Res., 17: 886-897; Faulkner et al. (2009) Nat. Genet., 41: 563-571; Lowe et al. (2007) Proc. Natl. Acad. Sci. USA, 104: 8005-8010; Mattick etal. (2009) Bioessays, 31: 51-59; Mercer etal. (2008) Proc. Natl. Acad. Sci. USA, 105: 716- 721 ; Mikkelsen et al., ed. (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells; Rozowsky et al. (2007) Genome Res., 17: 732-745; Trinklein et al. (2007) Genome Res., 17: 720-731). Recent studies have proven that retrotransposon transcriptional activities trigger and guide the processes of (i) assembly of centromeric chromatin, (ii) gene transcription, (iii) compartmentalization of chromatin and, (iv) nuclear organization of chromatin insulation during X-chromosome inactivation. Retrotransposons also serve a distinct function in non-random chromosomal translocations in tumors (Allen et al. (2004) Nat. Struct. Mol. Biol., 11: 816-821; Chueh etal. (2005) Hum. Mol. Genet., 14: 85-93; Lei and Corces (2006) Cell, 124: 886-888; Lei and Corces (2006) Nat. Genet., 38: 936-941; Lin et al. (2009) Cell, 139: 1069-1083; Lunyak (2008) Curr. Opin. Cell Biol, 20: 281-287; Lunyak et al. (2007) Science, 317: 248-251; Mattick et al. (2009) Bioessays, 31: 51-59; Navarro et al. (2009) Epigenetics Chromatin 2: 8). [0006] There is also a considerable amount of tissue-specific, development-specific, and disease-related variability in DNA methylation and covalent modifications of chromatin within the retrotransposal portion of the genome (Kondo and Issa (2003) J. Biol. Chem. 278: 27658-27662; Estecio et al. (2007) PLoS ONE 2: e399). A genome-wide study by Martens (Martens et al. (2005) EMBO J., 24: 800-8 12) demonstrates that LINEs, SINE/Alus, and other interspersed retrotransposons have variable degrees of H3K9, H3K27, and H4K20 histone methylation, raising the possibility that posttranscriptional modifications (PTM) of retrotransposal chromatin can influence diverse cellular processes. SUMMARY [0007] Efficient repair of DNA double-strand breaks and authentic genome maintenance at the chromatin level are fundamental to faithful human adult stem cell self- renewal. Stem cell aging can be linked to deficiencies in these two processes. In one example, we report that -65% of naturally occurring repairable damage in self-renewing adult stem cells occurs in transposable elements. Upregulation of transcriptional activity from SINE/Alu retrotransposons interferes with the recruitment of condensin I and cohesin complexes in pericentric chromatin, resulting in the loss of efficient DNA repair and, in turn, senescence. Stable knockdown of generic SINE/Alu transcripts in senescent human adult stem cells reinstates the cells self-renewing properties and unexpectedly increases their plasticity as manifested by upregulation of Nanog and Oct4. Our results demonstrate the functional significance of SINE/Alu retrotransposons and provide mechanistic insight into their novel role in mediating crosstalk between chromatin, DNA repair and aging of human adult stem cells. [0008] In certain embodiments, methods are provided for restoring a non-senescent phenotype, or aspects of a non-senescent phenotype to a senescent cell {e.g., a senescent adult stem cell). In certain embodiments, methods are provided for maintaining a non- senescent phenotype, or aspects of a non-senescent phenotype in a cell {e.g., a senescent adult stem cell).
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